In the past year we collaborated with labs that have produced knock-out models of the KSR1 and KSR2 genes, the ANKR26 gene, and the poly (ADP-ribose) polymerase 1 gene. The first three genes were knocked out to determine their role in oncogenesis, and the forth gene was knocked out to evaluate its role in ischemia/reperfusion injury. An unexpected feature of all of these knock-out animals was an obese phenotype. In addition to these 4 genes, we are also currently studying a human orexin gene receptor (HCRTR2) that has a role in energy metabolism in mice, and the PROX1 gene that results in adult onset of obsesity in mice. All of these genes have been directly sequenced in DNA samples from Pima Indians and all variants have been genotyped for assocation studies. We were able to confirm in humans, as observed in mice, that variation within KSR2 is associated with decreased energy expenditure (both as measured in a human respiratory chamber and a ventilated hood) and decreased physical activity (as measured by radar over 24 hours in a respiratory chamber). In contrast, we did not obeserve variantion in KSR1 that altered energy expenditure or predicted obesity in humans. Variation in ANKR26 did not contribute to the high prevalence of obesity in Pima Indians, nor was it associated with obesity among discordant Caucasian sibling pairs where genetic linkage to body mass index was previously observed in the genomic region that encompasses the ANKR26 gene. One variant in PROX1 was associated with obesity in Pima Indians. Our most significant findings were with HCRTR2, where the variaton that was associated with increased body weight was very common in the Pima population but this variation was not present among Caucasian populations, who are on average, much leaner.